1. Field of the Invention
The present invention relates to pheophorbide-α conjugates and their uses.
2. Description of the Related Art
Many drugs are designed based on the prodrug approach as the reason for improvement of physicochemical, biopharmaceutical or pharmacokinetic properties (Jarkko, R. et al., Nat. Rev. Drug Discov. 2008, 7, 225). Chemical linker, targeting-ligand, membrane transporter, and polymer have been used as the prodrug conjugation motives (Rubi, M. et al., Adv. Drug Deliv. Rev. 2011, 63, 659). As one of the targeting-ligand, photosensitizers have been utilized in the development of cancer diagnostic agents as well as in photodynamic therapy (PDT) which could treat cancer and non malignant tumor by reactive oxygen species generated by light, oxygen and photosensitizer (Sarika, V. et al., Photochem. Photobiol. 2007, 83, 996). Several photosensitizer conjugates have been developed. The carbohydrate moieties on conjugation with 3-(10-hexyloxyethyl)-3-devinyl pyropheophorbide-α (HPPH) (Xiang, Z et al., J. Med. Chem. 2009, 52, 4306), porphyrin conjugates with monocolonal antibodies (Karen, S. et al., Immunology 2010, 132, 256) and with spermine (Frank, H. et al., Chem. Med. Chem. 2008, 3, 1185), pyropheophorbide conjugate with tamoxifen (Ana, F. G. et al., J. Cell. Biochem. 2006, 99, 665), tetra(pentafluorophenyl)porphyrin conjugate with thiosaccharide (Xin, C. et al., Biochemistry 2004, 43, 10918), and Chlorin p6 and histamine conjugate (Arpana, P. et al., Cancer Chemother. Pharmacol. 2011, 68, 359) were reported to increase cellular accumulation of photosensitizer in tumor cells. In addition, anticancer drugs such as doxorubicin have been reported that their conjugated compounds enhanced selective cellular uptake and reduced the side effects (Yoshiyuki, Y. et al., Bioorg. Med. Chem. Lett. 2008, 18, 1632; Yu-Fen, H. et al., Chem. Biol. Chem. 2009, 10, 862; Paul, A. V. et al., on behalf of the Cancer Research Campaign Phase I/II Committee Clin. Cancer Res. 1999, 5, 83; Vanangamudi, A. N. C. et al., Biomed. Mater. Res. A 2010, 94A, 730). Pheophorbide-α (Pa, 1) is a chlorine based photosensitizer derived from chlorophyll-α with photo-dependent or -independent cytotoxic activity (Ritu, B. et al., J. Mol. Struct. 1994, 327, 201; Prapai, W. et al., Bioorg. Med. Chem. 2002, 10, 583).
The present inventors reported our investigations on the effects of pheophorbide-α conjugates with anticancer drugs such as doxorubicin (DOX, 2) and paclitaxel (PTX, 3) (FIG. 1) either by direct coupling or via linkers which are known for the characteristics of selective cleavage in cancer cell. The analysis of fluorescence spectrum, cellular uptake using confocal microscopy and in vitro anti-cancer activities in various cancer cell lines of the new pheophorbide-α conjugates are reported.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.